The overall goal of these studies is to understand the genetic contributions to autoimmune disease in murine models of systemic lupus erythematosus (SLE). This application will focus on (NZBxNZW)F/1 mice, which spontaneously produce IgG antinuclear antibodies and develop a fatal lupus-like renal disease. Genes from each parent (NZB and NZW) are necessary for full expression of the F/1 phenotype, and proposed studies in this application will attempt to further define both parental contributions. In previous studies from our laboratory, the major dominant NZW contribution was linked to the major histocompatibility complex (MHC; H-2/z in NZW). The experiments in Specific Aim 1 will continue transgenic studies examining whether class II genes (particularly I-A/z) have a pathogenetic role in the disease process. Related studies will examine whether differences in peptide binding determine the effect of various I-A molecules on disease expression. Non-MHC genes from NZW also appear to contribute to disease in a recessive fashion and the position of these loci will be determined. In Aim 2, proposed experiments will define the major dominant NZB genetic contribution to disease, which has been mapped to murine chromosome 4. Studies will attempt to narrow the interval that includes this NZB locus and to examine the possible relevance of certain candidate genes. Experiments in Aim 3 will focus on an additional NZB contribution mapped to chromosome 1, which is apparent in (NZBxSM/J) recombinant inbred and related backcross analyses. These studies will also better characterize a polygenic NZB contribution to disease that appears to operate in a threshold manner. Finally, experiments in Aim 4 will analyze the genetic contributions to a defect in apoptosis of resting B cells in (NZBxNZW)F/1 mice, and determine whether this defect is relevant to the development of lupus-like disease. The studies in this application will provide new insight into the genes that allow for autoimmune disease and the pathogenetic mechanisms that they induce. The results will also be important for a directed approach in studies of SLE patients.